Original ResearchFull Report: Basic and Translational—PancreasExclusion of T Cells From Pancreatic Carcinomas in Mice Is Regulated by Ly6Clow F4/80+ Extratumoral Macrophages
Section snippets
Animals
KPC mice have been described previously.12 Trp53LSL-R172H/+, Pdx1-Cre mice are syngeneic healthy littermates generated during routine breeding of KPC mice. All animal protocols were reviewed and approved by the Institute of Animal Care and Use Committee of the University of Pennsylvania.
Cell Lines
Tumor cell lines were developed from tumor tissue obtained from KPC mice as described previously.11
Tumor Studies
Mice were implanted subcutaneously with either a KPC tumor cell line (1 × 106 cells) or a 3 × 3 mm tumor chunk
Combination of Gemcitabine and a CD40 Agonist Produces T-Cell−Dependent Tumor Regressions in a Transplantable Model of Pancreatic Ductal Adenocarcinoma
Strong immunogenic tumor antigens expressed by pancreatic cancer cells arising in KPC mice are currently unknown. Therefore, to induce tumor-specific T-cell immunity, we used a vaccine approach in which gemcitabine chemotherapy is combined with a CD40 agonist.13 To examine this approach, syngeneic littermate Trp53R172H;Pdx-1-Cre mice implanted with pancreatic tumor cell lines derived from immunocompetent KPC mice were treated with gemcitabine and FGK45, an agonist antibody recognizing CD40 (
Discussion
Immune evasion is fundamental to tumor development. Malignant cells can evade immune elimination through a process of immunoediting in which cells adapt to immune pressure by losing their antigenicity and/or by gaining immunosuppressive properties.26 However, increasing evidence supports a role for nonmalignant cells in regulating immune escape in cancer. For example, developing tumors can orchestrate a complex stromal reaction that is immunosuppressive. In PDAC, fibroblasts, TAMs, MDSCs, and
Acknowledgments
The authors are grateful for advice from members of the Beatty and Vonderheide laboratories during preparation of this manuscript. The authors thank Qian-Chun Yu and Hongwei Yu for advice and technical assistance.
References (38)
- et al.
Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer
Cancer Cell
(2012) - et al.
Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice
Cancer Cell
(2005) - et al.
A Listeria vaccine and depletion of T-regulatory cells activate immunity against early stage pancreatic intraepithelial neoplasms and prolong survival of mice
Gastroenterology
(2014) - et al.
Immunosurveillance of pancreatic adenocarcinoma: insights from genetically engineered mouse models of cancer
Cancer Lett
(2009) - et al.
Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia
Cancer Cell
(2012) - et al.
Macrophage regulation of tumor responses to anticancer therapies
Cancer Cell
(2013) - et al.
CD40 engagement up-regulates cyclooxygenase-2 expression and prostaglandin E2 production in human lung fibroblasts
J Immunol
(1998) - et al.
CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans
Science
(2011) - et al.
Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer
J Immunother
(2013) - et al.
Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma
J Immunother
(2010)
Safety and activity of anti-PD-L1 antibody in patients with advanced cancer
N Engl J Med
Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer
Proc Natl Acad Sci U S A
Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer
Science
Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells
Nat Med
Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma
J Clin Oncol
Cancer genome landscapes
Science
Targeted depletion of an MDSC subset unmasks pancreatic ductal adenocarcinoma to adaptive immunity
Gut
Synergy between chemotherapy and immunotherapy in the treatment of established murine solid tumors
Cancer Res
CD4+ T lymphocyte ablation prevents pancreatic carcinogenesis in mice
Cancer Immunol Res
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Conflicts of interest These authors disclose the following: Gregory L. Beatty received research funding from Novartis. Robert H. Vonderheide received research funding from Pfizer and Roche. The remaining authors disclose no conflicts.
Funding This work was supported by grants from the National Institutes of Health to G.L.B. (NIH K08 CA138907), to R.W. (T32 CA009140), and to R.H.V. (R01 CA169123), from the Damon Runyon Cancer Research Foundation, for which G.L.B. is Nadia's Gift Foundation Innovator of the Damon Runyon-Rachleff Innovation Award (DRR-15-12), a Molecular Biology and Molecular Pathology and Imaging Cores of the Penn Center for the Molecular Studies in Digestive and Liver Diseases grant (P30 DK050306) from the Pancreatic Cancer Action Network and American Association of Cancer Research (R.H.V.), and by the Abramson Family Cancer Research Institute (R.H.V.).
Author names in bold designate shared co-first authorship.
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Authors share co-second authorship.